Hypothetical steps in the etiology of type 2 diabetes. If there is a defect in the leptin signaling system that lowers the
sympathetic activity, as seen in animal models, fatty acid oxidation capacity in the muscle will decrease (possibly by altering
the ACC/CPT I axis). This will increase the IMCL concentration, which will lower glucose uptake, leading to insulin resistance.
To compensate for the decreased insulin sensitivity in muscle, the pancreas increases insulin secretion to maintain NGT. Chronic
hyperinsulinemia further diminishes fatty acid oxidation, raising the concentration of fatty acyl-CoA and TG, and interferes
with the transport/phosphorylation pathways associated with normal glucose uptake. An elevated concentration of insulin will
also increase the output of VLDL by the liver. Circulating VLDL will deposit in the muscle and adipose tissue, which in the
early stages of the disease will increase fat deposition. If on top of this hyperphagia is added, the situation deteriorates.
Eventually, the ability of the adipose tissue to reesterify FFA is overwhelmed, increasing their concentration in plasma.
Excessive FFA will enhance glucose production by the liver, precipitating IGT. In an early stage, the increase of plasma FFA
will exacerbate the already existing hyperinsulinemia. Later, they will, through their lipotoxic effect, lead to β-cell failure
and overt type 2 diabetes.